As resources become less accessible – both in terms of funding and personnel - smaller or emerging sponsors are unlikely to have a large Chemistry, Manufacturing and Controls (CMC) group. In fact, in many cases, there may only be a single support individual within the whole organization.
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CMC activities from pre-IND to Phase 2 and beyond are often coordinated by this individual, and this work is often undertaken alongside other existing responsibilities. Many of these (often virtual) sponsors, however, employ contract manufacturing organizations (CMOs) to manage the CMC elements of their development and manufacturing.
In early-phase development, resources can be limited, and these are often earmarked for CMC activities which do not significantly contribute to the overall program.
Because of the average background of employees in small innovator organizations, the person responsible will usually possess very limited direct experience in working with GMPs or CMC development. Additionally, managing the full range of outsourced CMC activities for even one in development product can be challenging for a single individual.
The CMC essentials
While the main purpose of a CMC strategy is satisfying the obligations required for regulatory filings, the actual process of developing a robust CMC program can provide both immediate and long-term benefits, for example reduced development costs and the avoidance of needless delays.
The CMC essentials outlined in regulations and guidance(s) are designed to ensure that a drug is manufactured safely and consistently, from testing right through to commercialization and during the drug’s post-approval lifecycle.
A range of ICH and FDA guidance documents, books, presentations and articles provide a great deal of information on these processes.
Each drug candidate possesses unique characteristics, patient groups, dosage forms, and other factors, meaning that a standardized approach to CMC development may not be a viable option.
To effectively tailor a program, organizations must start by understanding the drug and its distinct characteristics. Establishing and documenting a quality target product profile, critical process parameters and critical quality attributes in early development phases will allow companies to cultivate a comprehensive understanding of both process requirements and change control for the product’s lifecycle.
Clinical trial milestones
Managing an innovator drug through its development, clinical trials, regulatory approval and eventual market launch is often a difficult balancing act. Small innovator companies which have limited time, expertise and resources available, may struggle to address the vital elements of drug development, because their focus is frequently on the drug’s clinical trial pathway.
The progress and external funding of a new drug is generally measured via the achievement of clinical trial milestones. These trials are designed to evaluate the drug’s safety and efficacy, meaning that formulation and manufacturing processes should be developed along with analytical methods capable of characterizing the drug.
These analytical methods must be able to effectively test the drug’s stability, potency and impurity profile, alongside a number of other properties.
Details on the drug, its properties, appropriate test methods, and its manufacturability must also be documented for regulatory filings, as outlined in the CMC section of its investigational new drug application (IND).
Sponsors must develop a strategy for manufacturing processes, applying the same level of detail that they give to clinical studies.
These plans should include information on the way in which the product will be supplied, how much product is needed for its clinical phase, what will be needed for its launch, and how each of these production processes should be validated.
Thoroughly planning a phase-appropriate approach is essential to avoid filing an incorrect amount of information, at an inappropriate point in the process. FDA provides the complete set of requirements for CMC filings in 21 CFR 312.
The regulations specify that the CMC section of an IND should accurately describe the composition, manufacture and control of the drug substance and related drug product.
Organizations are often unsure about how much information needs to be filed with the FDA, and when this information should be submitted. This uncertainty may lead to confusion, as well as cost overruns and delays in the development and/or clinical trial approval process.
CMC activities are varied, and can include the establishment of product characteristics and manufacturing processes, as well as identifying product testing methods to confirm product effectiveness, safety, and consistency between batches. In order to minimize any risks of later-stage failure, a number of vital CMC areas should be explored in early development.
Any decision to accelerate a development plan should ensure that it does not compromise the CMC work necessary in maintaining an adequate level of control, as defined by the industry and regulator.
Important CMC considerations in early development should include a comparison of use phase-appropriate analytical methods against fully validated methods, alongside a comprehensive understanding of the product’s development history.
A number of other issues should be considered, particularly those that relate to safety assessment, the drug substance’s solid state (salt and polymorph form), transition from early-phase to late-phase commercial and clinical dosage forms, and transition from small scale manufacturing process trains to multi-product process trains.
FDA’s website provides over 70 guidance documents in its Pharmaceutical Quality/CMC category. These documents clearly show FDA’s view on the requirements for various clinical phases, analytical testing methods, different drug types, and appropriate post-approval changes.
It should also be noted that FDA recommends specific agency-sponsor meetings be held to discuss CMC-related questions ahead of any IND filings.
No shortcuts and short timelines
Drugs that obtain a breakthrough therapy (BT) designation are presented with several CMC related challenges, for example a lack of commercial manufacturing supply chain availability.
In this instance, it would be necessary to launch the drug with preliminary commercial supplies sourced from a clinical trial manufacturing facility. In this scenario, there would be limited data available for setting specification acceptance criteria, alongside a reduction in the real-time stability of commercial materials.
FDA endeavors to be increasingly flexible, allowing for an accelerated review process that requires less complete data on the manufacturing process and its validation, the product’s specifications, and its stability. While these relaxed requirements aim to speed up the approval process, FDA’s standard requirements do still apply.
However, the accelerated review process has actually complicated CMC efforts. The reduced timelines for clinical review result in sponsors having less time to develop and validate manufacturing processes, in comparison with conventional review timelines.
These accelerated development timelines could potentially result in there being insufficient time to complete the full range of ‘traditional’ CMC studies ready for approval. For example:
- There may be a reduction in real time stability for commercial material, resulting in the need to leverage stability information from development studies.
- Organizations may only possess limited manufacturing experience at commercial scales, presenting the opportunity to leverage life cycle validation principles.
- There may be a need to consider launching using initial commercial supplies from a clinical manufacturing facility, via the use of clinical fit-for-purpose formulations, before transitioning to a commercial formulation and plant immediately following approval.
- The formulation and process may be ready for transfer, but the commercial facility may not be ready or even unavailable.
- There may be limited data sets available from which to obtain specification acceptance criteria.
If there is insufficient time to properly undertake traditional CMC studies, breakthrough programs must prioritize resources in order to collate the information required to adequately support the filing.
Sponsors should anticipate required alterations in formulation and manufacturing. Raw material suppliers could also be required to commit to further post-approval activity, including additional stability data and studies to verify process robustness.
Strategic and operational outsourcing
Innovator organizations will often request external assistance from an array of service providers. These range from individual consultants and consultancies that offer CMC strategic guidance and oversight of the CMC program’s development, through to CMOs which manage the implementation of formulation and process development, manufacturing steps, product testing and validation.
Because of drug development’s overall complexity, smaller emerging sponsors are likely to rely on several CMO providers to undertake a range of product development and analytical testing process steps.
Contracting an external CMO for essential development tasks is often a worthwhile option, but the sponsor must oversee and effectively manage this process, while ensuring appropriate protections remain in place for the intellectual property associated with the drug and its development.
Large integrated pharma companies tend to have an inhouse regulatory affairs team and a specific technical operations group to deliver on CMC requirements and submissions. However, small emerging sponsors will commonly delegate these roles to individuals or small team, who also have other responsibilities within the organization.
Ensuring that the regulatory and technical expertise to complete CMC steps is available, while ensuring the cost-effective use of limited resources, may prove especially challenging for these sponsors.
Partnering and out licensing
Where sponsors are seeking development partners or looking to sell an asset, an effective CMC program may make the drug more appealing to potential buyers or partners.
Accurately defining manufacturing requirements early on in the development process does present challenges and risks, however.
Common CMC failures include a failure to identify crucial process parameters or a quality target profile. These can also include insufficient development and validation of proper assays for potency, stability, and other factors.
Additional risks may stem from a failure to employ quality risk management, improperly auditing suppliers or quality agreements, not characterizing raw materials properly or problems locating alternate suppliers. Vendor-related noncompliance issues may also hinder a drug sponsor’s cautiously defined CMC plans.
Shortages in CMC manufacturing information can create an obstruction in some applications. A complete response letter (CL) as a result of CMC deficiencies can delay drug approvals, as well as dismissing a partnership or terminating a license deal.
Regulatory realities and forthcoming expectations
Emerging innovator organizations may consider in-licensing a product, start to develop a compound while exploring initial funding options, or even face a disruption.
When this happens, it is expected that organizations will need to re-examine their strategy or assess options, looking at other inventive approaches and exceptional quality work products that are designed to improve a product’s development, approval, and marketing potential.
Whether an organization is utilizing a Chemistry, Manufacturing and Controls (CMC) strategy, managing CMC operations or creating CMC submission content for an emerging biotech, it is vital that the organizations focus on the essential CMC issues outlined above, building programs which successfully meet development obligations.
Organizations can be ready for any eventuality by ensuring that all appropriate documentation is in place. Then, when called to act, organizations can progress this process with confidence.
About DS InPharmatics LLC
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
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